title: Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice.
abstract: Tubular epithelial injury represents an underestimated but important cause of renal dysfunction in patients with cholestasis and advanced liver disease, but the underlying mechanisms are unclear. To address the hypothesis that accumulation and excessive alternative urinary elimination of potentially toxic bile acids (BAs) may contribute to kidney injury in cholestasis, we established a mouse model for detailed in vivo time course as well as treatment studies. Three-day common bile duct ligation (CBDL) induced renal tubular epithelial injury predominantly at the level of aquaporin 2-positive collecting ducts with tubular epithelial and basement membrane defects. This was followed by progressive interstitial nephritis and tubulointerstitial renal fibrosis in 3-, 6-, and 8-week CBDL mice. Farnesoid X receptor knockout mice (with a hydrophilic BA pool) were completely protected from CBDL-induced renal fibrosis. Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy.
  
  
  CONCLUSIONS
  We characterized a novel in vivo model for cholemic nephropathy, which offers new perspectives to study the complex pathophysiology of this condition. Our findings suggest that urinary-excreted toxic BAs represent a pivotal trigger for renal tubular epithelial injury leading to cholemic nephropathy in CBDL mice.
authors.affiliation: Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Department of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Krones
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Pollheimer
authors.forename: Andrea
authors.initials: A
authors.lastname: Thueringer
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.forename: Dagmar
authors.initials: D
authors.lastname: Silbert
authors.forename: Emina
authors.initials: E
authors.lastname: Halilbasic
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.forename: Geurt
authors.initials: G
authors.lastname: Stokman
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Wells
authors.forename: Kathrin
authors.initials: K
authors.lastname: Eller
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Rosenkranz
authors.forename: Gosta
authors.initials: G
authors.lastname: Eggertsen
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Cord
authors.initials: C
authors.lastname: Langner
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000009:adverse effects*; D002779:Cholestasis / Q000150:complications*; D003135:Common Bile Duct; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000139:chemically induced*; D007684:Kidney Tubules / Q000293:injuries; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000209:etiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated